Mutations in voltage-gated sodium channels are responsible for some forms of human epilepsy. Q54 transgenic mice have a mutation in the voltage-gated sodium channel Scn2a and are a model for this disorder. The disorder in these mice begins with short-duration partial seizures and progresses to status epilepticus and premature death. There is extensive cell loss and gliosis in the hippocampus, which resembles the hippocampal sclerosis in temporal lobe epilepsy patients. Clinical severity of the epilepsy phenotype is influenced by genetic background. Q54 mice that are congenic on the resistant C57BL/6J background have delayed onset of seizures and increased survival, compared to susceptible [SJL/J x C57BL/6J]F1s. This suggests that dominant genetic modifiers underlie the severity of the phenotype and may influence the susceptibility of the hippocampus to pathological changes. We will identify the modifier gene(s) that influence seizure susceptibility in Q54 transgenic mice by positional cloning. Although hippocampal neuronal loss and reorganization have been reported in patients for many years, it has been difficult to determine if the pathological changes precede or result from seizures. We will compare the time course of cell loss, synaptic reorganization and dentate granule cell neurogenesis in the hippocampus of resistant and susceptible Q54 mice to determine the relationship between cellular pathology and clinical severity. The interaction of the mutated sodium channel gene and the modifier gene(s) in Q54 transgenic mice provides a model of gene interaction affecting susceptibility to inherited epilepsy. Understanding of this modifier gene(s) will provide insights into the pathogenesis of epilepsy and may suggest novel therapeutic targets for the treatment of human epilepsy patients. This proposal addresses two important areas in epilepsy research pertinent to the program announcement (PAR-01-111 ): the genetic complexity of inherited epilepsy, and the role of neuronal injury in seizure susceptibility. These studies will provide a foundation for an independent epilepsy research program for Dr. Jennifer Kearney and will establish a new collaboration between Dr. Kearney and Dr. Jack Parent. This collaboration will combine Dr. Kearney's expertise in mouse genetics with Dr. Parent's expertise in hippocampal pathology.